Osteoporosis is a major health problem for women and men in the United States. Current treatments for osteoporosis, such as dietary calcium supplements, estrogen replacement therapy, bisphosphonates, and calcitonin, are aimed at decreasing the rate of bone resorption. Bone formation is eventually limited during antiresorptive therapy due to osteoblast/osteoclast coupling. Tetracycline and its derivatives are known to bind to the mineralization front of bone-inhibiting bone resorption, in addiition to inhibiting mammalian collagenase and parathyroid hormone- induced bone resorption. In vivo studies in rodents have found minocycline to increase bone formation, as well as inhibiting bone resorption. This study was designed to determine whether minocycline at 200 mg/day with 800 mg/day of calcium, and 400 IU of vitamin D can increase bone mineral density with minimal toxicity. Results of this study are based on the four women who entered the study. Further recruitment was unsuccessful. Of the four women randomized, all four were on minocycline. One patient discontinued the study at 4.5 months secondary to unexplained nausea, vomiting, and abdominal pain while on drug therapy and with rechallenge. Of the three that continued to the full year, minimal loss of bone mineral density was observed (average 0.016 mg/cm2 at femoral neck; 0.012 gm/cm2 at total spine). At six months, changes in bone mineral density were minimal at -0.007 femoral neck and 0.002 for total spine. Serum alkaline phosphatase demonstrated increases by 3 and 9.5 mg/dL at six and twelve months. In conclusion, this study was unable to demonstrate effects of minocycline in retardation of bone loss either by changes in bone mineral density or in serum alkaline phosphatase. Toxicity remains a concern in that one in four patients had significant side- effects.